Etoposide is one of the most important drugs available for the treatment of paediatric malignancies. Although there is evidence of schedule dependency for etoposide therapy in adults with small-cell lung cancer, the relevance of this observation to childhood cancers is uncertain. Prolonged parenteral or oral etoposide therapy has not yet shown a clear-cut advantage over intermittent treatment, and there are still no data to show that the administration of etoposide as a short intravenous (i.v.) daily infusion for 5 days does not represent acceptable therapy for primary disease. The pharmacokinetic variability seen with etoposide argues strongly for the use of pharmacologically guided dosing, and the introduction of etoposide phosphate will simplify both parenteral etoposide administration and the future evaluation of alternative etoposide schedules. Although the impact of molecular and cellular pharmacological investigations on the clinical use of etoposide has yet to be felt, the tools to perform these studies are now available and prospective trials can be designed. Such studies, performed in the setting of a pharmacologically guided trial to ensure control over pharmacokinetic variability, should identify the best way of treating children with etoposide.